DOCSLIB.ORG

Interleukin 7 Receptor Α Chain (IL7R) Shows Allelic and Functional

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Interleukin 7 Receptor Α Chain (IL7R) Shows Allelic and Functional ARTICLES Interleukin 7 receptor a chain (IL7R) shows allelic and functional association with multiple sclerosis Simon G Gregory1,9, Silke Schmidt1,9, Puneet Seth2, Jorge R Oksenberg3, John Hart1, Angela Prokop1, Stacy J Caillier3, Maria Ban4, An Goris5, Lisa F Barcellos6, Robin Lincoln3, Jacob L McCauley7, Stephen J Sawcer4, D A S Compston4, Benedicte Dubois5, Stephen L Hauser3, Mariano A Garcia-Blanco2, Margaret A Pericak-Vance8 & Jonathan L Haines7, for the Multiple Sclerosis Genetics Group Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor a chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P ¼ 2.9 Â 10–7). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. http://www.nature.com/naturegenetics The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer. Multiple sclerosis is the prototypical human demyelinating disease, which requires multiple sources and types of positive evidence to and numerous epidemiological, adoption and twin studies have implicate a candidate gene, can be used to integrate both statistical provided evidence for a strong underlying genetic liability1.The and functional data. disease is most common in young adults, with more than 90% of Using genomic convergence3, we identified 28 genes that were affected individuals diagnosed before the age of 55, and fewer than 5% differentially expressed in at least two of nine previous expression diagnosed before the age of 14. Females are two to three times more studies (Supplementary Table 1 online). We focused on three genes frequently affected than males2, and the disease course can vary (interleukin 7 receptor alpha chain (IL7R) [MIM: 146661], matrix substantially, with some affected individuals suffering only minor metalloproteinase 19 (MMP19) [MIM: 601807] and chemokine (C-C disability several decades after their initial diagnosis, and others motif) ligand 2 (CCL2) [MIM: 158105]) that had a previously © Group 2007 Nature Publishing reaching wheelchair dependency shortly after disease onset. The published or inferred functional role in multiple sclerosis and that complex etiology of the disease and the currently undefined molecular were not located within the MHC. Two of the three genes localize to mechanisms of multiple sclerosis suggest that moderate contributions previous regions of genetic linkage on 17q12 (CCL2)4 and 5p13.2 from multiple risk loci underlie the development and progression of (IL7R)5. We analyzed a large data set of 760 US families of European the disease. descent, including 1,055 individuals with multiple sclerosis, and Many different approaches, including genetic linkage, candidate identified a significant association with multiple sclerosis susceptibility gene association and gene expression studies, have been used (sum- only for a nonsynonymous coding SNP (rs6897932) within a key marized in ref. 2) to identify the genetic basis of multiple sclerosis. transmembrane domain of IL7R. We subsequently replicated this However, genetic linkage screens have failed to identify consistent initial significant association in three independent European popula- regions of linkage outside of the major histocompatibility complex tions or populations of European descent: 438 individuals with (MHC). Candidate gene studies have suggested over 100 different multiple sclerosis and 479 unrelated controls ascertained in the United associated genes, but there has not been consensus acceptance of any States, 1,338 individuals with multiple sclerosis and their parents such candidates. Similarly, gene expression studies have identified ascertained in northern Europe (the UK and Belgium) and 1,077 hundreds of differentially expressed transcripts, with little consistency individuals with multiple sclerosis and 2,725 unrelated controls also across studies. The alternative approach of genomic convergence3, ascertained in northern Europe. We show that rs6897932 affects 1Center for Human Genetics, and 2Center for RNA Biology and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA. 3Department of Neurology, University of California, San Francisco, California 94143, USA. 4Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. 5Section for Experimental Neurology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. 6School of Public Health, University of California, Berkeley, California 94720, USA. 7Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. 8Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. 9These two authors contributed equally to this work. Correspondence should be addressed to J.L.H. ([email protected]) or M.A.P.-V. ([email protected]). Received 22 February; accepted 18 June; published online 29 July 2007; doi:10.1038/ng2103 NATURE GENETICS ADVANCE ONLINE PUBLICATION 1 ARTICLES Table 1 Clinical characteristics of the family-based and case-control multiple sclerosis data sets US data set European data set Affected individuals from Affected individuals from family-based data set Cases Controls family-based data set Cases Controls (n ¼ 1,055) (n ¼ 438) (n ¼ 479) (n ¼ 1,338) (n ¼ 1,077) (n ¼ 2,725) Mean age (and range), 41.6 (21–60) 44.6 (24–61) in years Mean age at onset 29.8 (3–63) 31.9 (11–60) 27.1 (9–53) 33.6 (10–62) (and range), in years Number of females 784 (74.3) 299 (68.3) 318 (66.4) 987 (74.0) 738 (68.5) 1350 (49.5) (and percentage) Disease type: n (%) Relapsing-remitting 552 (52.3) 365 (83.3) – – 1,152 (86.1) 875 (81.2) Secondary progressive 260 (24.6) 54 (12.3) – Progressive-relapsing 16 (1.5) 3 (0.7) – NA NA – Primary progressive 43 (4.1) 14 (3.2) – 80 (6.0) 146 (13.6) – Missing 184 (17.4) 2 (0.5) – 106 (7.9) 56 (5.2) – Mean disease duration 13.6 (0–50) 9.9 (0–44) – 10.8 (0–39) 16.4 (0–57) – (and range), in years Family-based US data set: 760 families (197 with multiple affected relatives (multiplex families), 563 with a single affected individual). Family-based European data set: 1,338 trios. UK affected individuals from trios: 64.8% relapsing-remitting, 27.4% secondary progressive. Unrelated UK affected individuals: 45.9% relapsing-remitting, 32.6% secondary progressive. For Belgian affected individuals, relapsing-remitting and secondary progressive multiple sclerosis were grouped together as ‘bout-onset’. http://www.nature.com/naturegenetics alternative splicing of exon 6, leading to increased skipping of the CCL2 and MMP19 (Supplementary Table 2 online), although this exon. This is predicted to increase production of soluble interleukin 7 does not exclude the possibility of a small effect of variants in either receptor alpha chain (IL7Ra) for individuals carrying the risk allele at gene. In the 760 US families (Table 1), the SNP having the strongest rs6897932. Our results strongly implicate the IL7Ra-related immune association with multiple sclerosis was rs6897932 (P ¼ 0.0006 by the response pathway in the etiology of multiple sclerosis. pedigree disequilibrium test (PDT)6), a nonsynonymous coding SNP (T244I) in exon 6 of IL7R, followed by rs11567705 (P ¼ 0.002) and RESULTS rs13188960 (P ¼ 0.002) (Table 2 and Fig. 1). The latter SNPs are in Initial analysis of CCL2, MMP19 and IL7R in US families strong linkage disequilibrium (LD) with rs6897932 (r2 ¼ 0.97 for None of the SNPs genotyped in IL7R, CCL2 or MMP19 strongly rs11567705, r2 ¼ 0.95 for rs13188960). The result for rs6897932 was deviated from Hardy-Weinberg equilibrium in a sample of unrelated due to overtransmission of the major allele (C) to offspring affected affected (P 4 0.04) or unaffected (P 4 0.10) individuals (P ¼ 0.05 for with multiple sclerosis. The risk allele frequency was similar in rs6897932 in affected individuals). We did not find any statistically individuals with multiple sclerosis who did or did not carry the significant evidence for association with multiple sclerosis for SNPs in multiple sclerosis–associated alleles HLA-DRB1*1501/1503 (0.79 and © Group 2007 Nature Publishing Table 2 PDT analysis of IL7R SNPs Minor/major Amino acid Overall PDT SNP Position (bp) allele MAF Gene region Type change P value rs13188960a 35889076 T/G 0.24 Upstream 0.0023 rs7718919 35891753 T/G 0.13 Upstream 0.8707 rs1389832a 35894478 T/C 0.34 Intron 1 0.0804 rs1494558a 35896825 A/G 0.34 Exon 2 Nonsynonymous I66T 0.0249 rs11567705 35896909 G/C 0.24 Intron 2 0.0018 rs969128 35896916 G/A 0.13 Intron 2 0.9343 rs1494555a 35906947 C/T 0.33 Exon 4 Nonsynonymous V138I 0.0327 rs7737000 35907030 T/C 0.13 Exon 4 Synonymous H165H 0.6801 rs1494554a 35909629 C/A 0.29 Intron 5 0.7175 rs6897932a 35910332 T/C 0.24 Exon 6 Nonsynonymous T244I 0.0006 rs987107a 35910984 T/C 0.29 Intron 6 0.7856 rs987106a 35911350 T/A 0.47 Intron 6 0.0134 rs3194051a 35912031 G/A 0.29 Exon 8 Nonsynonymous I356V 0.7856 rs1494571 35915844 C/G 0.28 Downstream 0.9276 P values meeting the Bonferroni-corrected significance threshold and respective
Load more

Recommended publications
  • ENSG Gene Encodes Effector TCR Pathway Costimulation Inhibitory/Exhaustion Synapse/Adhesion Chemokines/Receptors
    ENSG Gene Encodes Effector TCR pathway Costimulation Inhibitory/exhaustion Synapse/adhesion Chemokines/receptors ENSG00000111537 IFNG IFNg x ENSG00000109471 IL2 IL-2 x ENSG00000232810 TNF TNFa x ENSG00000271503 CCL5 CCL5 x x ENSG00000139187 KLRG1 Klrg1 x ENSG00000117560 FASLG Fas ligand x ENSG00000121858 TNFSF10 TRAIL x ENSG00000134545 KLRC1 Klrc1 / NKG2A x ENSG00000213809 KLRK1 Klrk1 / NKG2D x ENSG00000188389 PDCD1 PD-1 x x ENSG00000117281 CD160 CD160 x x ENSG00000134460 IL2RA IL-2 receptor x subunit alpha ENSG00000110324 IL10RA IL-10 receptor x subunit alpha ENSG00000115604 IL18R1 IL-18 receptor 1 x ENSG00000115607 IL18RAP IL-18 receptor x accessory protein ENSG00000081985 IL12RB2 IL-12 receptor x beta 2 ENSG00000186810 CXCR3 CXCR3 x x ENSG00000005844 ITGAL CD11a x ENSG00000160255 ITGB2 CD18; Integrin x x beta-2 ENSG00000156886 ITGAD CD11d x ENSG00000140678 ITGAX; CD11c x x Integrin alpha-X ENSG00000115232 ITGA4 CD49d; Integrin x x alpha-4 ENSG00000169896 ITGAM CD11b; Integrin x x alpha-M ENSG00000138378 STAT4 Stat4 x ENSG00000115415 STAT1 Stat1 x ENSG00000170581 STAT2 Stat2 x ENSG00000126561 STAT5a Stat5a x ENSG00000162434 JAK1 Jak1 x ENSG00000100453 GZMB Granzyme B x ENSG00000145649 GZMA Granzyme A x ENSG00000180644 PRF1 Perforin 1 x ENSG00000115523 GNLY Granulysin x ENSG00000100450 GZMH Granzyme H x ENSG00000113088 GZMK Granzyme K x ENSG00000057657 PRDM1 Blimp-1 x ENSG00000073861 TBX21 T-bet x ENSG00000115738 ID2 ID2 x ENSG00000176083 ZNF683 Hobit x ENSG00000137265 IRF4 Interferon x regulatory factor 4 ENSG00000140968 IRF8 Interferon
    [Show full text]
  • A1068-CD86 Polyclonal Antibody
    BioVision 05/16 For research use only CD86 Polyclonal Antibody CATALOG NO: A1068-100 ALTERNATIVE NAMES: T-lymphocyte activation antigen CD86, Activation B7-2 antigen, B70, BU63, CTLA-4 counter-receptor B72, FUN-1, CD86, CD86, CD28LG2 Western blot analysis of CD86 in NCI-H292 cell line lysate AMOUNT: 100 µl IMMUNOGEN: KLH conjugated synthetic peptide between 269-298 amino acids from the C-terminal region of human CD86. MOLECULAR WEIGHT: 37 kDa HOST/ISOTYPE: Rabbit IgG SPECIES REACTIVITY: Human PURIFICATION: This antibody is purified through a protein A column, followed by peptide affinity purification. FORM: Liquid FORMULATION: Supplied in PBS with 0.09% (W/V) sodium azide. STORAGE CONDITIONS: Maintain refrigerated at 2-8°C for up to 6 months. For long term RELATED PRODUCTS storage store at -20°C in small aliquots to prevent freeze-thaw cycles. DESCRIPTION: This gene encodes a type I membrane protein that is a member of the immunoglobulin superfamily. This protein is expressed by Human CellExp™ B7-2 /CD86, human recombinant (Cat. No. 7496-10, -50) antigen-presenting cells, and it is the ligand for two proteins at the CD86 (Human) ELISA Kit (Cat. No. K4175-100) cell surface of T cells, CD28 antigen and cytotoxic T-lymphocyte- Human CellExp™LAG3 /CD223, human recombinant (Cat. No. 7278-10, -50) associated protein 4. Binding of this protein with CD28 antigen is a costimulatory signal for activation of the T-cell. Binding of this CD223 (LAG3) Polyclonal Antibody (Cat. No. A1067-100) protein with cytotoxic T-lymphocyte-associated protein 4 negatively regulates T-cell activation and diminishes the immune response.
    [Show full text]
  • Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples
    Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples Qiang Liu Chinese Academy of Medical Sciences & Peking Union Medical College Yihang Qi ( [email protected] ) Chinese Academy of Medical Sciences and Peking Union Medical College https://orcid.org/0000-0001- 7589-0333 Jie Zhai Chinese Academy of Medical Sciences & Peking Union Medical College Xiangyi Kong Chinese Academy of Medical Sciences & Peking Union Medical College Xiangyu Wang Chinese Academy of Medical Sciences & Peking Union Medical College Yi Fang Chinese Academy of Medical Sciences & Peking Union Medical College Jing Wang Chinese Academy of Medical Sciences & Peking Union Medical College Research Keywords: Cancer immunotherapy, CD223, LAG3, Immune response, Inammatory activity Posted Date: June 19th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-36422/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/33 Abstract Background Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, a large number of cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, is a protein Coding gene served as alternative inhibitory receptors to be targeted in the clinic. The impact of LAG3 on immune cell populations and co-regulation of immune response in breast cancer remained largely unknown. Methods To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from a total of 2994 breast cancer patients. Results We observed that LAG3 was closely correlated with major molecular and clinical characteristics, and was more likely to be enriched in higher malignant subtype, suggesting LAG3 was a potential biomarker of triple-negative breast cancer.
    [Show full text]
  • Diabetes in the Absence of LAG-3 Cutting Edge
    Cutting Edge: Accelerated Autoimmune Diabetes in the Absence of LAG-3 Maria Bettini, Andrea L. Szymczak-Workman, Karen Forbes, Ashley H. Castellaw, Mark Selby, Xiaoyu Pan, This information is current as Charles G. Drake, Alan J. Korman and Dario A. A. Vignali of September 24, 2021. J Immunol 2011; 187:3493-3498; Prepublished online 26 August 2011; doi: 10.4049/jimmunol.1100714 http://www.jimmunol.org/content/187/7/3493 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2011/08/26/jimmunol.110071 Material 4.DC1 http://www.jimmunol.org/ References This article cites 25 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/187/7/3493.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 24, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Cutting Edge: Accelerated Autoimmune Diabetes in the Absence of LAG-3 Maria Bettini,* Andrea L.
    [Show full text]
  • Point Mutation in CD19 Facilitates Immune Escape of B Cell Lymphoma from CAR-­T Cell Therapy
    Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-001150 on 6 October 2020. Downloaded from Point mutation in CD19 facilitates immune escape of B cell lymphoma from CAR- T cell therapy 1 1 1 1 1 1 Zhen Zhang, Xinfeng Chen, Yonggui Tian, Feng Li , Xuan Zhao, Jinyan Liu, 1 1,2,3,4 Chang Yao, Yi Zhang To cite: Zhang Z, Chen X, ABSTRACT relapses after CD19 CAR-T cell therapy are Tian Y, et al. Point mutation Background Tumor relapse due to mutation in CD19 can attributed to the antigen loss, indicating an in CD19 facilitates immune hinder the efficacy of chimeric antigen receptor (CAR)- T urgent need for investigating the mechanisms escape of B cell lymphoma from cell therapy. Herein, we focused on lymphoma patients CAR- T cell therapy. Journal underlying recurrence and for improving whose B cells exhibited a point mutation in CD19 of B cells 4 5 for ImmunoTherapy of Cancer the efficacy of CAR- T cell therapy. Inter- 2020; :e001150. doi:10.1136/ after CAR-T cell infusion. 8 + estingly, one of the specific mechanisms jitc-2020-001150 Methods The CAR- T and CD19 B cells from peripheral blood or bone marrow were assessed using flow of tumor escape that has been reported cytometry. Genome sequencing was conducted to identify suggests that exon mutations affecting the ► Additional material is + published online only. To view, the molecular characteristics of CAR- T and CD19 B cells CD19 gene and its splicing isoforms, leading please visit the journal online from pre-rela pse and postrelapse samples.
    [Show full text]
  • LAG-3: from Molecular Functions to Clinical Applications
    Open access Review J Immunother Cancer: first published as 10.1136/jitc-2020-001014 on 13 September 2020. Downloaded from LAG-3: from molecular functions to clinical applications Takumi Maruhashi , Daisuke Sugiura , Il- mi Okazaki , Taku Okazaki To cite: Maruhashi T, Sugiura D, ABSTRACT (PD-1) and cytotoxic T lymphocyte antigen Okazaki I, et al. LAG-3: from To prevent the destruction of tissues owing to excessive 4 (CTLA-4) significantly improved the molecular functions to clinical and/or inappropriate immune responses, immune outcomes of patients with diverse cancer applications. Journal for cells are under strict check by various regulatory ImmunoTherapy of Cancer types, revolutionizing cancer treatment. The mechanisms at multiple points. Inhibitory coreceptors, 2020;8:e001014. doi:10.1136/ success of these therapies verified that inhib- including programmed cell death 1 (PD-1) and cytotoxic jitc-2020-001014 itory coreceptors serve as critical checkpoints T lymphocyte antigen 4 (CTLA-4), serve as critical checkpoints in restricting immune responses against for immune cells to not attack the tumor Accepted 29 July 2020 self- tissues and tumor cells. Immune checkpoint inhibitors cells as well as self-tissues. However, response that block PD-1 and CTLA-4 pathways significantly rates are typically lower and immune-related improved the outcomes of patients with diverse cancer adverse events (irAEs) are also observed in types and have revolutionized cancer treatment. However, patients administered with immune check- response rates to such therapies are rather limited, and point inhibitors. This is indicative of the immune-rela ted adverse events are also observed in a continued need to decipher the complex substantial patient population, leading to the urgent need biology of inhibitory coreceptors to increase for novel therapeutics with higher efficacy and lower response rates and prevent such unwanted toxicity.
    [Show full text]
  • Lymphocyte Activation Gene-3 – the Expression and Function in the Immune System
    Lymphocyte Activation Gene-3 – the expression and function in the immune system Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-naturwissenschaftlichen Fakultät der Universität Basel von Malgorzata Kisielow aus Edmonton, Kanada Basel, 2006 Genehmigt von der Philosphisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Antonius Rolink und PD. Dr. Patrick Matthias Basel, den 24 Mai 2005 Prof. Dr. Hans-Jakob Wirz 2 Mojej Mamie Mojemu Tacie 3 TABLE OF CONTENTS ABBREVIATIONS 7 SUMMARY 9 1. INTRODUCTION 11 1.1. The immune system 11 1.1.1. Players of adaptive immunity 12 1.1.1.1. B lymphocytes 12 - B2 B cells 13 - B1 B cells 13 - Marginal zone B cells 14 1.1.1.2. T lymphocytes 14 - αβ T cells 15 Helper T cells 15 Cytotoxic T cells 16 Regulatory T cells 16 NK T cells 17 - γδ T cells 18 1.1.1.3. Antigen Presenting Cells 18 - Denritic cells 19 1.1.1.4. Natural Killer Cells 21 1.1.2. Lymphocyte homeostasis 21 1.1.3. T cell responses 22 1.1.4. T cell-B cell collaboration in B cell responses 24 - Germinal Center reaction 27 1.2. Lymphocyte Activation Gene-3 28 1.2.1. Identification and the predicted structure 28 1.2.2. LAG-3 expression pattern 31 1.2.3. Regulation of Lag-3 expression 33 1.2.4. Suggested function of LAG-3 35 1.2.5. Mode of action of LAG-3 36 1.2.6. LAG-3 and cancer 38 2. THESIS OBJECTIVES 40 3.
    [Show full text]
  • Impact of IL-27 on Regulatory T Cell Responses
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2013 Impact of IL-27 on regulatory T cell responses Aisling Catherine O'Hara University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, and the Medical Immunology Commons Recommended Citation O'Hara, Aisling Catherine, "Impact of IL-27 on regulatory T cell responses" (2013). Publicly Accessible Penn Dissertations. 906. https://repository.upenn.edu/edissertations/906 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/906 For more information, please contact [email protected]. Impact of IL-27 on regulatory T cell responses Abstract Interleukin (IL)–27 is a heterodimeric cytokine with potent inhibitory properties. Thus, mice that lack IL–27–mediated signaling develop exaggerated inflammatory responses during toxoplasmosis as well as other infections or autoimmune processes. While regulatory T (Treg) cells are critical to limit inflammation, their oler during toxoplasmosis is controversial because this infection results in a dramatic decrease in the total numbers of these cells associated with reduced levels of IL–2. Because IL–27 suppresses IL–2, we initially hypothesized that it was responsible for the Treg cell “crash”. Thus, we examined the role of IL–27 and IL–2 and their effects on Treg cells during toxoplasmosis. We observed that although IL–2 production is enhanced in the absence of IL–27, this was not sufficiento t rescue Treg cell frequencies during infection. Rather, our data indicated that IL–27 promoted an immunosuppressive Treg cell population that displayed a T helper 1 (TH1) phenotype, characterized by the expression of T–bet, CXCR3, IL–10 and interferon (IFN)–γ.
    [Show full text]
  • Circulating Exosomes Inhibit B Cell Proliferation and Activity
    cancers Article Circulating Exosomes Inhibit B Cell Proliferation and Activity Jan C. Schroeder , Lisa Puntigam, Linda Hofmann , Sandra S. Jeske, Inga J. Beccard, Johannes Doescher, Simon Laban, Thomas K. Hoffmann, Cornelia Brunner , , Marie-Nicole Theodoraki y and Patrick J. Schuler * y Department of Otorhinolaryngology and Head and Neck Surgery, Ulm University, 89075 Ulm, Germany; [email protected] (J.C.S.); [email protected] (L.P.); [email protected] (L.H.); [email protected] (S.S.J.); [email protected] (I.J.B.); [email protected] (J.D.); [email protected] (S.L.); T.hoff[email protected] (T.K.H.); [email protected] (C.B.); [email protected] (M.-N.T.) * Correspondence: [email protected]; Tel.: +49-731-500-59501 These authors contributed equally. y Received: 23 June 2020; Accepted: 24 July 2020; Published: 29 July 2020 Abstract: (1) Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by a distinctive suppression of the anti-tumor immunity, both locally in the tumor microenvironment (TME) and the periphery. Tumor-derived exosomes mediate this immune suppression by directly suppressing T effector function and by inducing differentiation of regulatory T cells. However, little is known about the effects of exosomes on B cells. (2) Methods: Peripheral B cells from healthy donors and HNSCC patients were isolated and checkpoint receptor expression was analyzed by flow cytometry. Circulating exosomes were isolated from the plasma of HNSCC patients (n = 21) and healthy individuals (n = 10) by mini size-exclusion chromatography.
    [Show full text]
  • Lag-3 Mediates Acute Rejection & Memory in Mouse Transplantation
    Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine January 2018 Lag-3 Mediates Acute Rejection & Memory In Mouse Transplantation Jeffrey Mark Erfe Follow this and additional works at: https://elischolar.library.yale.edu/ymtdl Recommended Citation Erfe, Jeffrey Mark, "Lag-3 Mediates Acute Rejection & Memory In Mouse Transplantation" (2018). Yale Medicine Thesis Digital Library. 3393. https://elischolar.library.yale.edu/ymtdl/3393 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact [email protected]. LAG-3 MEDIATES ACUTE REJECTION & MEMORY IN MOUSE TRANSPLANTATION A Thesis Submitted to the Yale University School of Medicine In Partial Fulfillment of the Requirements for the Degree of Doctor of Medicine By Jeffrey Mark Erfe, MPH 2018 1 LAG-3 MEDIATES ACUTE REJECTION & MEMORY IN MOUSE TRANSPLANTATION Jeffrey Mark Erfe, Chao Yang, Dorothy Ndishabandi, Ivy Rosales, Rebecca White, Paul S. Russell, Robert B. Colvin, Joren C. Madsen, and Alessandro Alessandrini. Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA. (Sponsored by George Tellides, Section of Cardiothoracic Surgery, Yale University School of Medicine, New Haven, CT) ABSTRACT: Lymphocyte Activation Gene-3 (LAG-3) is a soluble protein and transmembrane protein receptor expressed on lymphocytes such as immunosuppressive regulatory T cells. Our goal was to evaluate the effect of LAG-3 on transplantation outcomes, specifically rejection and cellular memory response to donor antigen, by comparing graft survival and IFN-l secretion to donor antigen in C57BL/6 LAG-3-/- versus wild-type mouse recipients of DBA/2 grafts.
    [Show full text]
  • Lymphocyte-Activation Gene 3 (LAG-3) Immune Pathway
    Lymphocyte-Activation Gene 3 (LAG-3) About LAG-3 LAG-3 Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein found on the cell surface of effector T cells and regulatory T cells (Tregs) and functions to control T cell response, activation and growth.1 TCR T cells are a type of white blood cell that are part of the immune system. Activation of cytotoxic T cells by antigens enables them to 1 kill unhealthy or foreign cells. Inactive T cell Antigen MHC Dendritic cell (APC) LAG-3 and LAG-3 and LAG-3 and Immune Function T Cell Exhaustion Cancer • After a T cell is activated to kill its • However, in certain situations where T • Because of its critical role in regulating target cell, LAG-3 expression is cells experience prolonged exposure to an exhaustion of cytotoxic T cells and Treg increased to turn off the immune antigen, such as cancer or chronic function, LAG-3 has become a target of response, so that the T cell does not go infection, the T cells become desensitized study in the cancer field. on to attack healthy cells.2 and lose their ability to activate and multiply in the presence of the antigen.4 • In cancer, LAG-3 expressing exhausted • Inhibition of the immune response is cytotoxic T cells and Tregs expressing accomplished through activation of • The desensitized T cell will also LAG-3 gather at tumor sites.5,6 the LAG-3 pathway, which can occur progressively fail to produce cytokines via binding of LAG-3 to a type of (proteins that assist in the immune • Preclinical studies suggest that inhibiting antigen-presenting complex called response) and kill the target cells.4 LAG-3 allows T cells to regain their MHC II.
    [Show full text]
  • Preclinical Development of the Anti-LAG-3 Antibody REGN3767
    Author Manuscript Published OnlineFirst on August 8, 2019; DOI: 10.1158/1535-7163.MCT-18-1376 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Characterization of the Anti-LAG-3 Antibody REGN3767 Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3 Knock-In Mice Elena Burova, Aynur Hermann, Jie Dai, Erica Ullman, Gabor Halasz, Terra Potocky, Seongwon Hong, Matt Liu, Omaira Allbritton, Amy Woodruff, Jerry Pei, Ashique Rafique, William Poueymirou, Joel Martin, Douglas MacDonald, William Olson, Andrew Murphy, Ella Ioffe, Gavin Thurston, and Markus Mohrs1 Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 1Corresponding author: Markus Mohrs, Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591. Phone: 914-847-1122; Fax: 914-847-7453; E-mail: [email protected] Running title: Characterization of human anti-LAG-3 antibody REGN3767 Keywords: LAG-3, Checkpoint blockade, Monoclonal antibody, Immunotherapy, Cancer Disclosure of Potential Conflicts of Interest All authors are employees of Regeneron Pharmaceuticals, but otherwise have no conflicts of interest to declare. Financial support statement This work is funded by Regeneron Pharmaceuticals, Inc. Electronic work count Abstract: 228 Words of text: 4684 Number of figures and tables Figures: 6 1 Downloaded from mct.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 8, 2019; DOI: 10.1158/1535-7163.MCT-18-1376 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]